Alpha-Ketoglutarate Inhibits Autophagy

The metabolite alpha-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl alpha-ketoglutarate (DMKG), trifluoromethylbenzyl alpha-ketoglutarate (TFMKG) and octyl alpha-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate alpha-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of alpha-ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular alpha-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect.